“Tremor” refers to rhythmic shaking of a body part. Tremor is one of the most common involuntary movement disorders seen in clinical practice. In addition to consideration of a detailed history, the differential diagnosis of tremor is mainly clinically based on the distinctions made at rest, postural or intention; activation condition; frequency; and topographical distribution. The causes of tremor are heterogeneous and a tremor can present alone (e.g., as with essential tremor) or as a part of a neurological syndrome, such as traumatic brain injury, hypoxic brain injury, cerebrovascular accident, and/or multiple sclerosis, etc. This latter type of tremor is referred to as “neurogenic tremor”.
Essential Tremor (ET) is the most common type of tremor. Although it is called a “benign” condition, essential tremor may be far from benign. Essential tremors may be frustrating, embarrassing, or even disabling to the patient. Essential tremor is a very common and complex neurological movement disorder. One characteristic of essential tremor is that it is not caused by another neurological condition or the side effect of a medication. ET usually affects the hands, but it may also affect the head and neck (causing shaking), face, jaw, tongue, voice (causing a shaking or quivering sound), the trunk and, rarely, the legs and feet. The tremor movement associated with ET may be a rhythmic “back-and-forth” or “to-and-fro” movement produced by involuntary contractions of the muscle. It is a syndrome characterized by a slowly progressive postural and/or kinetic tremor, usually affecting both upper extremities. The pathophysiology of ET is not known. No pathological findings are known to be associated consistently with ET. Essential tremors are characteristically postural (occurring with voluntary maintenance of a position against gravity) and kinetic (occurring during voluntary movement) and usually resolve when the body part relaxes. ET probably represents a syndrome and multiple etiologies have been identified. Most or all of these causes are probably genetic as evidenced by the fact that ET is familial in at least 50-70% of cases. Severity of the tremors can vary greatly from hour to hour and day to day. Some people experience ET only in certain positions, i.e. as a postural tremor. Tremor that worsens while writing or eating is called kinetic or action-specific tremor. Most people with ET have both postural and kinetic tremor.
Neurogenic tremors, on the other hand, occur as a part of a neurological syndrome, such as with traumatic brain injury, hypoxic brain injury, cerebrovascular accident, and/or multiple sclerosis, etc. As far as physical impairments following brain injury and/or neurological diseases are concerned, neurogenic tremors can be particularly debilitating. Neurogenic tremor is a movement disorder that is associated with rhythmic, involuntary muscular contractions of reciprocally innervated, antagonistic muscle groups characterized by rhythmic oscillations (“to-and-fro” movements) of a part of the body about a fixed plane in space. The most common of all involuntary movements, neurogenic tremor can affect various body parts such as the hands, head, facial structures, vocal cords, trunk and legs, although most tremors occur in the distal upper extremities; e.g. hands. Given that the upper extremities are most commonly affected, various aspects of activities of daily living (ADLs) can be adversely affected including self-feeding, fine motor manipulation, writing, and dressing, etc. Although neurogenic tremor is by no means life threatening, it can be the cause of significant functional disability and therefore require use of either adaptive aids and/or assistance from others to compensate for the impairment.
Generally, neurogenic tremors are manifest as the following sub-classifications of tremor “type”: resting, postural and kinetic.
1) “Resting tremor” occurs when the muscle is at rest, for example, when the hands on left lying on a surface. This type of tremor is normal 4 to 6 hertz in frequency with medium amplitude. This type of tremor is often seen in patients with Parkinson's disease. Currently treatment of resting tremors is predominantly focused in pharmacotherapies involving dopamine agonist drugs such as L-dopa, amantadine, and parlodel, etc., and anticholinergic agents, such as benztropine and trihexyphenidyl.
2) “Postural tremor” occurs when a patient attempts to maintain posture such as holding the hands outstretched. Postural tremors include physiological tremor, tremor associated basal ganglia disease/injury, cerebellar postural tremor, tremor with peripheral neuropathy, and alcoholic tremor. There is no established drug treatment for this type of tremor, although beta-blockers, isoniazid, anticonvulsants and other drugs have been used with some limited success.
3) “Kinetic tremor” occurs during purposeful movement, for example, during finger-to-nose testing. Kinetic tremors tend to be low frequency tremors and tend to occur ipsilateral to the side of cerebellar involvement, including but not limited to, the cerebellar outflow tracts. This type of tremor can also be seen with certain degenerative brain diseases. Numerous medications have been used, albeit with quite limited success, including but not limited to: beta-blockers, anticonvulsants, benzodiazepines, anticholinergics, and buspirone.
Symptomatic drug therapy is available for several types of neurogenic tremors. For example, for some types of neurogenic tremors there are specific pharmacological approaches to management of the tremors, such as anti-Parkinsonian drugs for Parkinson-related resting tremor. However, the majority of tremors do not have well established drug treatments, as determined either by practitioner consensus nor evidence based research. In addition, many of the drugs that are currently used to modulate tremor have also been noted to have potential and significant deleterious side effects including sedation, metabolic toxicities and/or cognitive depressant actions.
For those cases of tremor in which there is no effective drug treatment, physical measures such as teaching the patient to brace the affected limb during the tremor are sometimes useful. Physical treatments such as limb weighting have also been advocated for modulating certain types of tremor such as cerebellar postural tremor and kinetic tremor; however, these interventions tend to be cumbersome with difficulty maintaining patient compliance due to the perceived “socially unacceptability” of these modalities.
In addition, surgical intervention such as thalamotomy or deep brain stimulation may be useful in certain cases (Bogey et al: “Rehabilitation of movement disorders”, Arch Phys Med Rehabil. 85(Suppl 1): S41-45, 2004.
An intervention that is effective, easily transportable and has an acceptably low side effect profile would be ideal for modulating this type of disabling condition. Based on available evidence, the novel application of topical anesthetics for modulation of neurogenic tremor meets these criteria.
To date, topical anesthetics have never been proposed for use in treatment of neurogenic (e.g. neurological) tremors. The first study to suggest that tremor might be reduced, in any fashion, through treatment with anesthetics, although not through topically to the skin, was published in 1993 in Parrent et al., “Tremor Reduction by Microinjection ofLidocaine During Stereotactic Surgery”, Acta Neurochirurgica, 58:45-47 (1993). This study examined the effects of lidocaine microinjections into the thalami of ten patients undergoing stereotactic thalamotomy for the treatment of Parkinsonian or Parkinsonian tremor. In overall ⅔ of cases, the test, microinjection of the lidocaine replicated the effects of microstimulation. The authors concluded that longer term follow-up would be required to determine whether lesions made on the basis of lidocaine induced tremor suppression would result in a lower rate of tremor recurrence than those based on stimulation induced tremor suppression.
A study by Levy et al. “Lidocaine and Muscimol Microinjectionand Subthalamic NucleusReversed Parkinsonian Symptoms”, Brain 124(Pt10):2105-2118 (2001) demonstrated that application of lidocaine centrally in the subcortical areas of the brain ameliorated tremor through the inactivation of neuronal activity in the subthalamic nucleus; thereby, improving motor symptoms, possibly by alternating the oscillatory activity of neurons located beyond the inhibited area.
Finally, Pozos et al., “Effective Topical Anesthesiaon Essential Tremor”, Electromyography and Clinical Neurophysiology, 32(7-8): 369-72 (1992), looked at the effects of skin desensitization on essential tremor in study that used a single-blinded approach. The researchers found that topical anesthetic significantly suppressed essential tremor amplitude and associated electrical activity in all patients with the mean tremor amplitude being reduced by 40%. However, there was no apparent follow up study that has either replicated this finding and unfortunately treatments developed for the treatment of essential tremor have not proved to be indicative of efficacy in treating neurogenic tremors.